This proposal is designed to investigate the role of leptin receptor (LEPR) in brain areas implicated in the regulation of energy balance, and to characterize the subtler phenotypic effects of partial leptin receptor downregulatlon. Leptin-deficient mice (ob/ob) are hyperphagic and obese, a syndrome that is corrected by administration of leptin. The signaling form of LEPR (LEPR-B) is highly expressed in the hypothalamus, and mice deficient in LEPR-B (db/db) are likewise obese but are not leptin responsive. Several studies in mice heterozygous for LEPR deficiency (db/+) suggest that reduced levels of LEPR elicit a partial phenotype predisposed to metabolic dysregulation. The specific goals of this proposal are to assess the contribution of forebrain neurons to body weight regulation and adiposity, and to test the hypothesis that gene dosage of LEPR in the forebrain determines the severity of the obese phenotype. In Specific Aim 1, mice with LEPR deleted in forebrain neurons (Lepr null) will be characterized to assess the contribution of leptin signaling to body weight regulation. In Specific Aim 2, LEPR-B will be overexpressed in forebrain neurons using a tetracycline-responsive promoter (Tet-LEPR) to rescue the obese phenotype of LEPR-deficient mice. In Specific Aim 3, LEPR-B expression will be reversibly suppressed in Tet-LEPR mice to establish a dose-response curve for Lepr gene dosage and its impact on several metabolic parameters. In situ hybridization of LEPR and hypothalamic peptides that regulate body weight (NPY, AGEP, POMC and CART) will be performed in addition to behavioral tests. These studies will help to advance our understanding of brain LEPR signaling and the effects of LEPR heterozygosity on phenotype.